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Exome sequencing reveals a novel partial deletion in the progranulin gene causing primary progressive aphasia

Authors:
Jonathan Rohrer at University College London
Jonathan Rohrer
Jon Beck at NeoGenomics Laboratories
Jon Beck
Vincent Plagnol
Vincent Plagnol
Vincent Plagnol
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Elizabeth Gordon at Qynapse
Elizabeth Gordon
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Abstract and Figures

In 2005, we reported a case of familial primary progressive aphasia (PPA) in this journal.1 The individual in question had a family history of frontotemporal dementia (FTD), her brother having behavioural variant FTD shown to be due to tau-negative, ubiquitin-positive (FTLD-U) pathology at postmortem. She was followed as part of a research programme from the age of 51 years, first developing symptoms of progressive speech disturbance at the age of 55 years. We were able to demonstrate the emergence of neuropsychometric deficits and brain atrophy prior to symptom onset. Through the use of voxel compression mapping, we showed the emergence of very focal, presymptomatic regional atrophy initially almost entirely confined to the pars opercularis (figure 1A).1 Over time, the atrophy spread through the frontal and temporal lobes to affect the parietal lobe and then the right frontal lobe. Subsequent analysis has shown increase in left and right hemispheric lobar atrophy prior to symptom onset, although the left hemisphere volume loss preceded and remained more prominent than the right throughout the disease course (figure 1B). Figure 1 MRI changes in the proband: (A) sagittal MRI showing focal anterolateral left frontal lobe atrophy, particularly centred around the pars opercularis, using voxel compression mapping between the first and second scans (3.4 …
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Exome sequencing reveals a novel partial deletion in the progranulin gene causing primary progressive aphas
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LETTER
Exome sequencing reveals a
novel partial deletion in the
progranulin gene causing
primary progressive aphasia
In 2005, we reported a case of familial
primary progressive aphasia (PPA) in this
journal.
1
The individual in question had a
family history of frontotemporal dementia
(FTD), her brother having behavioural
variant FTD shown to be due to tau-
negative, ubiquitin-positive (FTLD-U)
pathology at postmortem. She was fol-
lowed as part of a research programme
from the age of 51 years, first developing
symptoms of progressive speech disturb-
ance at the age of 55 years. We were able
to demonstrate the emergence of neurop-
sychometric deficits and brain atrophy
prior to symptom onset. Through the use
of voxel compression mapping, we
showed the emergence of very focal,
presymptomatic regional atrophy initially
almost entirely confined to the pars oper-
cularis (figure 1A).
1
Over time, the
atrophy spread through the frontal and
temporal lobes to affect the parietal lobe
and then the right frontal lobe.
Subsequent analysis has shown increase in
left and right hemispheric lobar atrophy
prior to symptom onset, although the
left hemisphere volume loss preceded
and remained more prominent than the
right throughout the disease course
(figure 1B).
At the time of publication, mutations in
the microtubule-associated protein tau
(MAPT) were the only known genetic
cause of disorders within the FTD spec-
trum, and screening for MAPT mutations
was negative. Since then, the progranulin
(GRN) and C9ORF72 genes have been
shown to be major causes of familial
FTD.
2
Her brother’s pathology was subse-
quently reanalysed and reclassified as
FTLD-transactive response DNA-binding
protein (TDP) type A pathology,
3
consist-
ent with either a GRN or C9ORF72
mutation. However, conventional analyses
failed to disclose mutations in either of
these genes in this family.
4–6
In order to investigate this further, DNA
from her brother underwent exome sequen-
cing, performed on genomic DNA using
Agilent SureSelect Human All Exon v2
target enrichment kit. Sequencing was per-
formed on an Illumina HiSeq2000 and
achieved an average 30-fold depth-of-cover-
age of target sequence.
7
ExomeDepth
8
compares the read depth data between a
test sample and an aggregate reference set
that combines multiple exomes matched to
the test sample for technical variability
(Software freely available at: http://cran.
r-project.org/web/packages/ExomeDepth/
index.html). Analysis demonstrated a GRN
gene deletion. The red crosses (figure 2)
show the ratio of observed/expected
number of reads for the test sample. The
grey shaded region shows the estimated
99% CI for this observed ratio in the
absence of copy number variation (CNV)
call. The presence of contiguous exons with
read count ratio located outside of the CI is
indicative of a heterozygous deletion in the
GRN gene. GRN exons 0, 2, 5, 9 and 11
were subsequently probed for copy number
variation using multiplex ligation-
dependent probe amplification (MLPA)
analysis with the Medical Research Council
(MRC) Holland kit P275, which is rou-
tinely used for assessing GRN deletions.
910
This confirmed the presence of a novel het-
erozygous deletion of exons 2–11. Test
results show the 50untranslated region of
the gene was present, but could not deter-
mine if exon 12 of GRN was also deleted.
The same deletion was detected in the
proband using MLPA analysis.
While progranulin mutations were not
known to cause frontotemporal lobar
degeneration at the time of our original
report, the clinical features that emerged
during the course of her illness would now
be recognised as being fairly characteristic.
Progranulin mutations are usually asso-
ciated with behavioural variant FTD or
PPA,
23
with combinations of these presen-
tations recognised within the same family.
Neuropsychologically, patients often have
executive dysfunction and early parietal
lobe deficits, with PPA patients having a
non-fluent aphasia with a prominent
anomia. Imaging studies in patients with
established disease typically show promin-
ent asymmetrical atrophy affecting frontal,
temporal and parietal lobes consistent with
neuropsychological findings.
11
Finally, the
pathology, type A TDP-43, would be con-
sistent with that seen in progranulin muta-
tions (and also C9ORF72 expansions).
23
This case serves to illustrate a number
of important points. First, progranulin
Figure 1 MRI changes in the proband: (A) sagittal MRI showing focal anterolateral left frontal lobe atrophy, particularly centred around the pars
opercularis, using voxel compression mapping between the first and second scans (3.4 and 2.1 years prior to symptom onset) (reprinted from
Janssen et al,
1
; (B) changes in left and right hemispheric volume over time.
J Neurol Neurosurg Psychiatry December 2013 Vol 84 No 12 1411
PostScript
mutations should always be considered as
a cause of PPA where there is a positive
family history either of PPA or behav-
ioural variant FTD. Second, prominent
asymmetric lobar atrophy on MRI is an
important clue to the presence of a pro-
granulin rather than a MAPT or
C9ORF72 mutation in the context of an
autosomal-dominant family history. Third,
as with other neurodegenerative diseases,
this case shows that focal brain atrophy
precedes symptom onset in genetically
determined forms of FTD; rates of
atrophy may therefore be useful outcome
measures for presymptomatic therapeutic
trials in these disorders. Finally, the fact
that conventional progranulin testing was
negative in this case demonstrates the
power of exome sequencing as a tool to
discover large-scale mutations, such as the
partial deletion seen here, that may not be
found with usual screening methods for
small-scale changes.
Jonathan D Rohrer,
1
Jonathan Beck,
2
Vincent Plagnol,
3
Elizabeth Gordon,
1
Tammaryn Lashley,
4
Tamas Revesz,
4
John C Janssen,
5
Nick C Fox,
1
Jason D Warren,
1
Martin N Rossor,
1
Simon Mead,
2
Jonathan M Schott
1
1
Dementia Research Centre, Department of
Neurodegenerative Disease, UCL Institute of Neurology,
London, UK
2
MRC Prion Unit, Department of Neurodegenerative
Disease, UCL Institute of Neurology, London, UK
3
Department of Statistics, Institute of Genetics,
University College London, UK
4
Queen Square Brain Bank, UCL Institute of Neurology,
London, UK
5
Department of Neurology, Chelsea and Westminster
Hospital, London, UK
Correspondence to Dr Jonathan M Schott, Institute
of Neurology –Dementia Research Centre, Queen
Square, London WC1N 3BG, UK;
j.schott@ucl.ac.uk
Acknowledgements This work was funded by the
Medical Research Council UK. The Dementia Research
Centre is an Alzheimer’s Research UK Co-ordinating
Centre and has also received equipment funded by
Alzheimer’s Research UK and Brain Research Trust. JR
is an NIHR clinical lecturer, MR and NF are NIHR senior
investigators, JDW is supported by a Wellcome Trust
Senior Clinical Fellowship, and are researchers at the
NIHR Queen Square Dementia BRU. JS is an NIHR
Clinical Senior Lecturer. This work was supported by
the NIHR Queen Square Dementia BRU.
Contributors JDR wrote the draft of the manuscript
and analysed the imaging data. JB, VP and SM
performed the genetic analyses. TL and TR performed
the pathological analyses. EG performed imaging
analyses. JCJ, JMS, MNR, JDW and NCF performed
patient evaluation. All authors reviewed and
contributed to the final manuscript.
Competing interests None.
Ethics approval Ethical approval for the study was
obtained from the National Hospital for Neurology and
Neurosurgery Local Research Ethics Committee.
Provenance and peer review Not commissioned;
externally peer reviewed.
Open Access This is an Open Access article
distributed in accordance with the terms of the Creative
Commons Attribution (CC BY 3.0) license, which
permits others to distribute, remix, adapt and build
upon this work, for commercial use, provided the
original work is properly cited. See: http://
creativecommons.org/licenses/by/3.0/
To cite Rohrer JD, Beck J, Plagnol V, et al.J Neurol
Neurosurg Psychiatry 2013;84:1411–1412.
J Neurol Neurosurg Psychiatry 2013;84:1411–1412.
doi:10.1136/jnnp-2013-306116
REFERENCES
1 Janssen JC, Schott JM, Cipolotti L, et al. Mapping
the onset and progression of atrophy in familial
frontotemporal lobar degeneration. J Neurol
Neurosurg Psychiatry 2005;76:162–8.
2 Rohrer JD, Warren JD. Phenotypic signatures of
genetic frontotemporal dementia. Curr Opin Neurol
2011;24:542–9.
3 Rohrer JD, Lashley T, Schott JM, et al. Clinical and
neuroanatomical signatures of tissue pathology in
frontotemporal lobar degeneration. Brain 2011;134
(Pt 9):2565–81.
4 Beck J, Rohrer JD, Campbell T, et al. A distinct
clinical, neuropsychological and radiological
phenotype is associated with progranulin gene
mutations in a large UK series. Brain 2008;
131(Pt 3):706–20.
5 Rohrer JD, Guerreiro R, Vandrovcova J, et al. The
heritability and genetics of frontotemporal lobar
degeneration. Neurology 2009;73:1451–6.
6 Mahoney CJ, Beck J, Rohrer JD, et al. Frontotemporal
dementia with the C9ORF72 hexanucleotide repeat
expansion: clinical, neuroanatomical and
neuropathological features. Brain 2012;135(Pt
3):736–50.
7 Sergouniotis PI, Davidson AE, Mackay DS, et al.
Biallelic mutations in PLA2G5, encoding group V
phospholipase A2, cause benign fleck retina. Am J
Hum Genet 2011;89:782–91.
8 Plagnol V, Curtis J, Epstein M, et al. A robust model
for read count data in exome sequencing
experiments and implications for copy number
variant calling. Bioinformatics 2012;28:2747–54.
9 Gijselinck I, van der Zee J, Engelborghs S, et al.
Progranulin locus deletion in frontotemporal
dementia. Hum Mutat 2008;29:53–8.
10 Skoglund L, Ingvast S, Matsui T, et al. No evidence
of PGRN or MAPT gene dosage alterations in a
collection of patients with frontotemporal lobar
degeneration. Dement Geriatr Cogn Disord
2009;28:471–5.
11 Rohrer JD, Ridgway GR, Modat M, et al. Distinct
profiles of brain atrophy in frontotemporal lobar
degeneration caused by progranulin and tau
mutations. Neuroimage 2010;53:1070–6.
Figure 2 The read count ratio of observed to expected is shown plotted against position in
basepairs along chromosome 17. A reduction in read count ratio to 0.5 and below at the GRN
locus can be seen, and indicate a heterozygous gene deletion.
1412 J Neurol Neurosurg Psychiatry December 2013 Vol 84 No 12
PostScript
... To substantiate this relationship further, we provide a brief account of the genetic aetiology of PPA and NDDs like Alzheimer's disease (AD), Parkinson's disease (PD), and dyslexia. For instance, GRN and C9orf72 are the most commonly associated genes with PPA that are also associated with NDDs (Mahoney et al. 2012;Rohrer et al. 2013). Apart from these genes, the risk of PPA increases with the mutation of KIAA0319 that is primarily known to cause dyslexia (Paternicó et al. 2015). ...
... It is known that these conditions fall under the FTLD spectrum. The genes associated with FTLD spectrum are GRN, C9orf72, FOXP2, VCP and MAPT (Padovani et al. 2010;Kim et al. 2011;de Jong et al. 2012;Mahoney et al. 2012;Rohrer et al. 2013). Among these, only GRN and C9orf72 are commonly associated with PPA syndrome through individual case studies. ...
... These sporadic case studies of GRN mutation for PPA raise a question regarding its distinctiveness. Rohrer et al. (2013) closely analysed the neuro-molecular anatomy of PPA patients and substantiated the claim that GRN mutation is the molecular reason for PPA, especially with nfvPPA. Conversely, when GRN mutation is negative in PPA patients, C9orf72 gene is considered for the molecular cause, as there is an overlap between the expansion of C9orf72 and PPA (Renton et al. 2011;Mahoney et al. 2012;Van Langenhove et al. 2013). ...
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  • Sep 2019
Primary progressive aphasia (PPA) is a progressive neurodegenerative disease that disrupts the language capacity of an individual by selectively affecting the language network of brain. Although aphasic literature is replete with reports of brain damage responsible for various types of PPA, it does not provide a comprehensive understanding of whether PPA is an independent pathological condition or an atypical syndrome of neurodegenerative diseases (NDD). To address this ambiguity, we provide a detailed description of PPA, its variants and their brain anatomy. Subsequently, we unravel the relationship between PPA and NDDs like Alzheimer’s, Parkinson’s and Dyslexia. To substantiate the relationship further, we also provide a brief account of their genetic aetiology. In the final section, we offer an exhaustive approach towards the treatment of PPA by combining the existing language therapies with clinical and pharmacological interventions.
View
... All these mutations result in haploinsufficiency due to the degradation of the mutant GRN transcript through nonsense-mediated decay and, consequently, in reduced levels of the progranulin protein (www.molgen.vib-ua.be/ADMutations/). Complete or near-complete genomic GRN deletions are very rare; they have been described in only three families [8][9][10]. Reduced GRN levels in plasma predict GRN mutations in FTLD patients with high sensitivity and specificity [11][12][13][14]. ...
... A complete deletion of GRN and two neighbouring genes (RPIP8, SLC25A39) and two nearly complete GRN gene deletions including exons 2 to 12 had previously been identified [8][9][10]. In this study, we found, for the first time, heterozygous partial deletions removing only one or two GRN exons. ...
Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration
Article
Full-text available
  • Jan 2014
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Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD). Most known GRN mutations are null mutations, such as nonsense and frameshift mutations, which create a premature stop codon resulting in loss of function of the progranulin protein. Complete or near-complete genomic GRN deletions have also been found in three families, but heterozygous partial deletions that remove only one or two exons have not been reported to date. In this study, we analysed three unrelated FTLD patients with low plasma progranulin levels but no point GRN mutations by multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF). We detected two heterozygous partial GRN deletions in two patients. One deletion removed exon 1 and part of intron 1. The second deletion was complex: it removed 1,410 bp extending from the part of intron 1 to the part of exon 3, with a small 5-bp insertion at the breakpoint junction (c.-7-1121_159delinsGATCA). Our findings illustrate the usefulness of a quantitative analysis in addition to GRN gene sequencing for a comprehensive genetic diagnosis of FTLD, particularly in patients with low plasma progranulin levels.
View
... This leads to degradation of mutant mRNA due to nonsense-mediated decay, resulting in reduction of PGRN levels [2,3]. Rare complete or nearly complete deletions of GRN have also been described [6][7][8]. To date, only one research group reported a partial deletion of one or two exons [9]. ...
Two novel variants in GRN: the relevance of CNV analysis and genetic screening in FTLD patients with a negative family history
Article
Full-text available
  • Dec 2024
  • J NEUROL
Background Frontotemporal lobar degeneration (FTLD) is one of the leading causes of early onset dementia. Pathogenic variants in GRN have been reported to cause 5–25% of familial and 5% of sporadic FTLD. Here, we present two novel, likely pathogenic variants in GRN. Methods Four patients from four different families underwent whole exome sequencing (WES) with additional copy-number variance (CNV) analysis in a clinical setting. TMEM106B rs1990622 and rs3173615 SNPs and 3’UTR insertion were tested in one presymptomatic carrier. In three probands and one presymptomatic carrier, plasma progranulin (PGRN) levels were measured using a specific ELISA kit. In two probands, neuropathological diagnosis was established using current neuropathological criteria. Results Through CNV analysis on WES data, we identified a partial deletion, NM_002087.2 (GRN):c.1179 + 104_1536delinsCTGA, p.(?), in three patients with primary progressive aphasia and/or corticobasal syndrome. Haplotype analysis revealed a shared haplotype block, suggesting that the deletion represents a founder mutation. Additionally, we found a novel, missense variant, NM_002087.2 (GRN):c.23 T > A, p.(Val8Glu), in one proband with a negative family history. The proband’s unaffected parent—in their 80 s—carried the same variant, yet was homozygous for the TMEM106B risk haplotype. The pathogenicity of both GRN variants was supported by typical neuropathological features and reduced PGRN levels. Conclusion We recommend a thorough genetic screening, including CNV analysis, for both familial and apparent sporadic FTLD patients. Furthermore, the presymptomatic carrier homozygous for the TMEM106B risk haplotype exemplifies the presence of other protective factors that modify disease onset and urges caution in genetic counselling based on the TMEM106B haplotype.
View
... These can lead to splice donor site read-through followed by nuclear retention and degradation or to a premature stop codon, triggering degradation of the mutant transcript by nonsense-mediated mRNA decay [33]. Additionally, partial or complete deletions of the progranulin locus have been identified [199][200][201][202]. ...
The Development of Drug Therapies for Frontotemporal Dementia Caused by Progranulin Mutations
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  • May 2015
In this chapter, we discuss the development of therapies for frontotemporal dementia caused by progranulin mutations. Although this is a relatively rare and very specific form of neurodegeneration, the upstream disease cause, being haploinsufficiency of the growth factor progranulin, offers straightforward opportunities for therapy development. Substitution of the progranulin deficiency is likely to counteract the detrimental effects of progranulin haploinsufficiency in patients with frontotemporal dementia and may prevent the manifestation of the disease in presymptomatic mutation carriers. As progranulin has neurotrophic and anti-inflammatory properties, therapeutic interventions aimed at augmenting progranulin levels may also become useful in other forms of neurodegeneration.
View
... Few studies of mutation carriers at risk of frontotemporal dementia have been done, and investigators of these studies have reported inconsistent fi ndings (appendix). [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] Although fi ndings from some studies have shown presymptomatic changes in neuropsychometric testing near to disease onset, 9,11,[15][16][17]22 others have not shown any changes. 13,19,21,[23][24][25] Similarly, fi ndings from a few case studies 9,11,17 and small case series 12,13,18 have shown evidence of grey matter volume loss before symptoms onset with structural MRI, but other studies have reported no abnormalities. ...
Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: A cross-sectional analysis
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  • Feb 2015
Background: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia. Methods: We recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers. Findings: Between Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1). Interpretation: Structural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. Funding: Centres of Excellence in Neurodegeneration.
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... This approach is based on the prior hypothesis that such loss-of-function mutations are more likely to cause severe phenotypic effects commonly seen in rare diseases. A number of studies have also identified exonic copy number variation (CNV) as the underlying genetic basis for various Mendelian disorders (Lango Allen et al., 2014;Rohrer et al., 2013). ...
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  • Aug 2012
  • BIOINFORMATICS
Motivation: Exome sequencing has proven to be an effective tool to discover the genetic basis of Mendelian disorders. It is well established that copy number variants (CNVs) contribute to the etiology of these disorders. However, calling CNVs from exome sequence data is challenging. A typical read depth strategy consists of using another sample (or a combination of samples) as a reference to control for the variability at the capture and sequencing steps. However, technical variability between samples complicates the analysis and can create spurious CNV calls. Results: Here, we introduce ExomeDepth, a new CNV calling algorithm designed to control for this technical variability. ExomeDepth uses a robust model for the read count data and uses this model to build an optimized reference set in order to maximize the power to detect CNVs. As a result, ExomeDepth is effective across a wider range of exome datasets than the previously existing tools, even for small (e.g. one to two exons) and heterozygous deletions. We used this new approach to analyse exome data from 24 patients with primary immunodeficiencies. Depending on data quality and the exact target region, we find between 170 and 250 exonic CNV calls per sample. Our analysis identified two novel causative deletions in the genes GATA2 and DOCK8. Availability: The code used in this analysis has been implemented into an R package called ExomeDepth and is available at the Comprehensive R Archive Network (CRAN). Contact: v.plagnol@ucl.ac.uk Supplementary Information: Supplementary data are available at Bioinformatics online.
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Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features
Article
Full-text available
  • Mar 2012
  • BRAIN
An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43-68 years) and duration (1.7-22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration-TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.
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Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration
Article
Full-text available
  • Sep 2011
  • BRAIN
Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.
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Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations
Article
Full-text available
  • Nov 2010
  • NEUROIMAGE
Neural network breakdown is a key issue in neurodegenerative disease, but the mechanisms are poorly understood. Here we investigated patterns of brain atrophy produced by defined molecular lesions in the two common forms of genetically mediated frontotemporal lobar degeneration (FTLD). Nine patients with progranulin (GRN) mutations and eleven patients with microtubule-associated protein tau (MAPT) mutations had T1 MR brain imaging. Brain volumetry and grey and white matter voxel-based morphometry (VBM) were used to assess patterns of cross-sectional atrophy in the two groups. In a subset of patients with longitudinal MRI rates of whole-brain atrophy were derived using the brain-boundary-shift integral and a VBM-like analysis of voxel-wise longitudinal volume change was performed. The GRN mutation group showed asymmetrical atrophy whereas the MAPT group showed symmetrical atrophy. Brain volumes were smaller in the GRN group with a faster rate of whole-brain atrophy. VBM delineated a common anterior cingulate-prefrontal-insular pattern of atrophy in both disease groups. Additional disease-specific profiles of grey and white matter loss were identified on both cross-sectional and longitudinal imaging: GRN mutations were associated with asymmetrical inferior frontal, temporal and inferior parietal lobe grey matter atrophy and involvement of long intrahemispheric association white matter tracts, whereas MAPT mutations were associated with symmetrical anteromedial temporal lobe and orbitofrontal grey matter atrophy and fornix involvement. The findings suggest that the effects of GRN and MAPT mutations are expressed in partly overlapping but distinct anatomical networks that link specific molecular dysfunction with clinical phenotype.
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Mapping the onset and progression of atrophy in familial frontotemporal lobar degeneration
Article
Full-text available
  • Mar 2005
Frontotemporal lobar degeneration (FTLD) may be inherited as an autosomal dominant disease. Studying patients "at risk" for developing FTLD can provide insights into the earliest onset and evolution of the disease. We carried out approximately annual clinical, MRI, and neuropsychological assessments on an asymptomatic 51 year old "at risk" family member from a family with FTLD associated with ubiquitin-positive and tau-negative inclusion bodies. We used non-linear (fluid) registration of serial MRI to determine areas undergoing significant regional atrophy at different stages of the disease. Over the first 26 months of the study, the patient remained asymptomatic, but subsequently developed progressive speech production difficulties, and latterly severe orofacial dyspraxia, dyscalculia, frontal executive impairment, and limb dyspraxia. Regional atrophy was present prior to the onset of symptoms, and was initially centred on the left dorsolateral prefrontal cortex and the left middle frontal gyrus. Latterly, there was increasing asymmetric left frontal and parietal atrophy. Imaging revealed excess and increasing global atrophy throughout the study. Neuropsychological evaluation revealed mild intellectual impairment prior to the onset of these clinical symptoms; frontal executive and left parietal impairment subsequently emerged, culminating in widespread cognitive impairment. Fluid registered MRI allowed the emerging atrophy patterns to be delineated. We have demonstrated the onset and progressive pattern of in vivo atrophy in familial FTLD using fluid registered MRI and correlated this with the clinical features. Fluid registered MRI may be a useful technique in assessing patterns of focal atrophy in vivo and demonstrating the progression of degenerative diseases.
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Biallelic Mutations in PLA2G5, Encoding Group V Phospholipase A2, Cause Benign Fleck Retina
Article
  • Nov 2011
  • AM J HUM GENET
Flecked-retina syndromes, including fundus flavimaculatus, fundus albipunctatus, and benign fleck retina, comprise a group of disorders with widespread or limited distribution of yellow-white retinal lesions of various sizes and configurations. Three siblings who have benign fleck retina and were born to consanguineous parents are the basis of this report. A combination of homozygosity mapping and exome sequencing helped to identify a homozygous missense mutation, c.133G>T (p.Gly45Cys), in PLA2G5, a gene encoding a secreted phospholipase (group V phospholipase A(2)). A screen of a further four unrelated individuals with benign fleck retina detected biallelic variants in the same gene in three patients. In contrast, no loss of function or common (minor-allele frequency>0.05%) nonsynonymous PLA2G5 variants have been previously reported (EVS, dbSNP, 1000 Genomes Project) or were detected in an internal database of 224 exomes (from subjects with adult onset neurodegenerative disease and without a diagnosis of ophthalmic disease). All seven affected individuals had fundoscopic features compatible with those previously described in benign fleck retina and no visual or electrophysiological deficits. No medical history of major illness was reported. Levels of low-density lipoprotein were mildly elevated in two patients. Optical coherence tomography and fundus autofluorescence findings suggest that group V phospholipase A(2) plays a role in the phagocytosis of photoreceptor outer-segment discs by the retinal pigment epithelium. Surprisingly, immunohistochemical staining of human retinal tissue revealed localization of the protein predominantly in the inner and outer plexiform layers.
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Phenotypic signatures of genetic frontotemporal dementia
Article
  • Dec 2011
  • CURR OPIN NEUROL
Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous disorder. Mutations in a number of genes are associated with FTD, although until recently only two [progranulin (GRN) and microtubule-associated protein tau (MAPT)] were known to be major causes of the disease. This review describes recent progress in identifying clinical and neuroanatomical phenotypes associated with autosomal-dominant FTD. Around a third to a half of FTD patients have an autosomal dominant pattern of inheritance. Up to 10% of patients have a mutation in GRN and a similar proportion have a mutation in MAPT. Recently a group of patients have been shown to have a hexanucleotide repeat expansion in the noncoding region of chromosome 9 open reading frame 72 (C9ORF72). A further group of patients have an autosomal dominant family history but no mutations in any of the known genes including a group of patients who have the same pathology as GRN mutations (type A TDP-43 pathology) but are negative for GRN mutations. Clinical phenotypes vary across the different mutations. Neuroimaging studies show that GRN and MAPT mutations have distinct patterns of atrophy--asymmetric fronto-temporo-parietal atrophy with GRN versus relatively symmetric medial temporal and orbitofrontal lobe atrophy with MAPT mutations. Neuroimaging of patients with an expansion in C9ORF72 has yet to be studied in detail. Genetic FTD is heterogeneous but certain phenotypic signatures of the major causative genes can be identified.
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No Evidence of PGRN or MAPT Gene Dosage Alterations in a Collection of Patients with Frontotemporal Lobar Degeneration
Article
  • Nov 2009
  • DEMENT GERIATR COGN
Alterations in gene dosage have recently been associated with neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, and deletions of the progranulin (PGRN) locus were recently described in patients with frontotemporal lobar degeneration (FTLD). FTLD is a genetically complex neurodegenerative disorder with mutations in the PGRN and the microtubule-associated protein tau (MAPT) genes being the most common known causes of familial FTLD. In this study, we investigated 39 patients with FTLD, previously found negative for mutations in PGRN and MAPT, for copy number alterations of these 2 genes. Gene dosage analysis of PGRN and MAPT was performed using multiplex ligation-dependent probe amplification. We did not identify any PGRN or MAPT gene dosage variations in the 39 FTLD patients investigated. We therefore conclude that alterations in gene copy number of PGRN and MAPT are not a cause of disease in this collection of FTLD patients.
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The heritability and genetics of frontotemporal lobar degeneration
Article
  • Nov 2009
  • NEUROLOGY
Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder. We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease. A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1). These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.
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Progranulin locus deletion in frontotemporal dementia
Article
Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated.
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